Andrew S. Kennedy

Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: Early results in 148 patients

Purpose:The use of 90Y-microspheres to treat unresectable liver metastases originating from a variety of neuroendocrine tumors was reviewed. Materials and Methods:This is a retrospective review from 10 institutions of patients given 90Y-microsphere therapy for neuroendocrine hepatic metastases. Physical, radiographic, biochemical, and clinical factors associated with treatment and response were examined. All patients were followed with laboratory and imaging studies at regular intervals until death, or censured whether other therapy was given after brachytherapy. Toxicities (acute and late) were recorded, and survival of the group determined. Results:A total of 148 patients were treated with 185 separate procedures. The median age was 58 years (26–95 years) at treatment with median performance status of Eastern Cooperative Oncology Group (0). The median activity delivered was 1.14 GBq (0.33–3.30 GBq) with a median of 99% of the planned activity able to be given (38.1%–147.4%). There were no acute or delayed toxicity of Common Terminology Criteria for Adverse Events v3.0 grade 3 in 67% of patients, with fatigue (6.5%) the most common side effect. Imaging response was stable in 22.7%, partial response in 60.5%, complete in 2.7% and progressive disease in 4.9%. No radiation liver failure occurred. The median survival is 70 months. Conclusion:Radioembolization with 90Y-microspheres to the whole liver, or lobe with single or multiple fractions are safe and produce high response rates, even with extensive tumor replacement of normal liver and/or heavy pretreatment. The acute and delayed toxicity was very low without a treatment related grade 4 acute event or radiation induced liver disease in this modest-sized cohort. The significant objective response suggests that further investigation of this approach is warranted.

Treatment Parameters and Outcome in 680 Treatments of Internal Radiation With Resin 90Y-Microspheres for Unresectable Hepatic Tumors

PURPOSE Radioembolization (RE) using (90)Y-microspheres is an effective and safe treatment for patients with unresectable liver malignancies. Radiation-induced liver disease (RILD) is rare after RE; however, greater understanding of radiation-related factors leading to serious liver toxicity is needed. METHODS AND MATERIALS Retrospective review of radiation parameters was performed. All data pertaining to demographics, tumor, radiation, and outcomes were analyzed for significance and dependencies to develop a predictive model for RILD. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria Adverse Events Version 3.0 scale. RESULTS A total of 515 patients (287 men; 228 women) from 14 US and 2 EU centers underwent 680 separate RE treatments with resin (90)Y-microspheres in 2003-2006. Multifactorial analyses identified factors related to toxicity, including activity (GBq) Selective Internal Radiation Therapy delivered (p < 0.0001), prescribed (GBq) activity (p < 0.0001), percentage of empiric activity (GBq) delivered (p < 0.0001), number of prior liver treatments (p < 0.0008), and medical center (p < 0.0001). The RILD was diagnosed in 28 of 680 treatments (4%), with 21 of 28 cases (75%) from one center, which used the empiric method. CONCLUSIONS There was an association between the empiric method, percentage of calculated activity delivered to the patient, and the most severe toxicity, RILD. A predictive model for RILD is not yet possible given the large variance in these data.

Radioembolization with 90Y Microspheres: Angiographic and Technical Considerations

The anatomy of the mesenteric system and the hepatic arterial bed has been demonstrated to have a high degree of variation. This is important when considering pre-surgical planning, catheterization, and trans-arterial hepatic therapies. Although anatomical variants have been well described, the characterization and understanding of regional hepatic perfusion in the context of radioembolization have not been studied with great depth. The purpose of this review is to provide a thorough discussion and detailed presentation of the angiographic and technical aspects of radioembolization. Normal vascular anatomy, commonly encountered variants, and factors involved in changes to regional perfusion in the presence of liver tumors are discussed. Furthermore, the principles described here apply to all liver-directed transarterial therapies.

90Y radioembolization for metastatic neuroendocrine liver tumors: Preliminary results from a multi-institutional experience

Purpose:Minimally invasive therapies such as transarterial chemoembolization and radiofrequency ablation are used for hepatic metastatic neuroendocrine tumor (NET) therapy. Results from another minimally invasive therapy, radioembolization, remain unknown. The purpose of this multicenter open label phase II study was to assess the efficacy and safety of yttrium-90 (90Y) radioembolization for treating hepatic metastatic NET using a primary outcome of tumor response and secondary outcomes of serologic toxicities and survival. Material/Methods:In this multicenter study, all patients underwent lobar radioembolization using glass or resin 90Y radioembolic agents. Patients were assessed serologically and radiographically at 2 to 4 weeks and then at 1 to 3 month intervals after treatment. We 1) compared liver volumes, radiation doses, and serologic liver function tests (unpaired t test, P = 0.05) and 2) assessed tumor response, serologic toxicity, and median survival from first 90Y therapy. The clinicaltrials.gov identifier was NCT00532740. Results:Forty-two patients underwent radioembolization using glass (mean age 58 ± 12 years) or resin (mean age 61 ± 11 years) microspheres. A statistically significant greater median radiation dose was delivered to each lobe using glass (right lobe 117 Gy; left lobe 108 Gy) than using resin (right 50.8 Gy; left 44.5 Gy) (P < 0.01). Using Response Criteria in Solid Tumors, 92% of glass and 94% of resin patients were classified as partial response or stable disease at 6 months after treatment. Six patients experienced grade 3/4 toxicities during the follow-up period. Median survival was 22 months (glass) and 28 months (resin) (P = 0.82). Conclusion:90Y radioembolization of metastatic NET is a viable therapy with acceptable toxicity. Further investigation is warranted.

Recommendations of the American Association of Physicists in Medicine on dosimetry, imaging, and quality assurance procedures for 90Y microsphere brachytherapy in the treatment of hepatic malignancies.

Yttrium-90 microsphere brachytherapy of the liver exploits the distinctive features of the liver anatomy to treat liver malignancies with beta radiation and is gaining more wide spread clinical use. This report provides a general overview of microsphere liver brachytherapy and assists the treatment team in creating local treatment practices to provide safe and efficient patient treatment. Suggestions for future improvements are incorporated with the basic rationale for the therapy and currently used procedures. Imaging modalities utilized and their respective quality assurance are discussed. General as well as vendor specific delivery procedures are reviewed. The current dosimetry models are reviewed and suggestions for dosimetry advancement are made. Beta activity standards are reviewed and vendor implementation strategies are discussed. Radioactive material licensing and radiation safety are discussed given the unique requirements of microsphere brachytherapy. A general, team-based quality assurance program is reviewed to provide guidance for the creation of the local procedures. Finally, recommendations are given on how to deliver the current state of the art treatments and directions for future improvements in the therapy.

Patient selection and activity planning guide for selective internal radiotherapy with yttrium-90 resin microspheres.

PURPOSE Selective internal radiotherapy (SIRT) with yttrium-90 ((90)Y) resin microspheres can improve the clinical outcomes for selected patients with inoperable liver cancer. This technique involves intra-arterial delivery of β-emitting microspheres into hepatocellular carcinomas or liver metastases while sparing uninvolved structures. Its unique mode of action, including both (90)Y brachytherapy and embolization of neoplastic microvasculature, necessitates activity planning methods specific to SIRT. METHODS AND MATERIALS A panel of clinicians experienced in (90)Y resin microsphere SIRT was convened to integrate clinical experience with the published data to propose an activity planning pathway for radioembolization. RESULTS Accurate planning is essential to minimize potentially fatal sequelae such as radiation-induced liver disease while delivering tumoricidal (90)Y activity. Planning methods have included empiric dosing according to degree of tumor involvement, empiric dosing adjusted for the body surface area, and partition model calculations using Medical Internal Radiation Dose principles. It has been recommended that at least two of these methods be compared when calculating the microsphere activity for each patient. CONCLUSIONS Many factors inform (90)Y resin microsphere SIRT activity planning, including the therapeutic intent, tissue and vasculature imaging, tumor and uninvolved liver characteristics, previous therapies, and localization of the microsphere infusion. The influence of each of these factors has been discussed.

Research Reporting Standards for Radioembolization of Hepatic Malignancies

Primary Liver Tumors Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver; its incidence is increasing worldwide. It ranks as the sixth most common tumor and third most common cause of cancer-related mortality (1,2). Primary liver tumors include HCC and intrahepatic cholangiocarcinoma. Surgical resection is preferred over transplantation and is considered potentially curative in patients with resectable HCC and normal liver function (3). Transplantation is considered the gold standard for patients with unresectable HCC and whose disease is within the Milan criteria (4). Resection and transplantation have limited roles, given advanced disease (chronic liver disease and/or tumor extent) at presentation and limited organ availability (5–7). Chemoembolization and radiofrequency ablation represent standard therapies in treating patients and serve as a bridge to transplantation in selected patients (8,9). Radioembolization has an emerging role in “bridging” patients within criteria by delaying tumor progression. It has also been shown to downstage disease beyond the Milan, to within, transplant criteria (10–12). A recent study has demonstrated that radioembolization leads to longer time-to-progression and better toxicity profile when compared with chemoembolization (13). Patients with macrovascular tumor involvement have also exhibited evidence of clinical benefit after radioembolization (14).

Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: The tumor selectivity of the treatment as a function of tumor to liver flow ratio

BackgroundTreatment records and follow-up data on 40 patients with primary and metastatic liver malignancies who underwent a single whole-liver treatment with Y-90 resin microspheres (SIR-Spheres® Sirtex Medical, Lake Forest, IL) were retrospectively reviewed. The objective of the study was to evaluate the anatomic and physiologic determinants of radiation dose distribution, and the dose response of tumor and liver toxicity in patients with liver malignancies who underwent hepatic arterial Y-90 resin microsphere treatment.MethodsLiver and tumor volume calculations were performed on pre-treatment CT scans. Fractional tumor and liver flow characteristics and lung shunt fractions were determined using hepatic arterial Tc-99m MAA imaging. Absorbed dose calculations were performed using the MIRD equations. Liver toxicity was assessed clinically and by liver function tests. Tumor response to therapy was assessed by CT and/or tumor markers.ResultsOf the 40 patients, 5 had hepatocellular cancer (HCC), and 35 had metastatic liver tumors (15 colorectal cancer, 10 neuroendocrine tumors, 4 breast cancer, 2 lung cancer, 1 ovarian cancer, 1 endometrial cancer, and 2 unknown primary adenocarcinoma). All patients were treated in a salvage setting with a 3 to 80 week follow-up (mean: 19 weeks). Tumor volumes ranged from 15.0 to 984.2 cc (mean: 294.9 cc) and tumor to normal liver uptake ratios ranged from 2.8 to 15.4 (mean: 5.4). Average administered activity was 1.2 GBq (0.4 to 2.4 GBq). Liver absorbed doses ranged from 0.7 to 99.5 Gy (mean: 17.2 Gy). Tumor absorbed doses ranged from 40.1 to 494.8 Gy (mean: 121.5 Gy). None of the patients had clinical venoocclusive disease or therapy-induced liver failure. Seven patients (17.5 %) had transient and 7 patients (17.5 %) had persistent LFT abnormalities. There were 27 (67.5%) responders (complete response, partial response, and stable disease). Tumor response correlated with higher tumor flow ratio as measured by Tc-99m MAA imaging.ConclusionDoses up to 99.5 Gy to uninvolved liver are tolerated with no clinical venoocclusive disease or liver failure. The lowest tumor dose producing a detectable response is 40.1 Gy. The utilization of MAA-based imaging techniques to determine tumor and liver blood flow for clinical treatment planning and the calculation of administered activity may improve clinical outcomes.

Incidence of radiation pneumonitis after hepatic intra-arterial radiotherapy with yttrium-90 microspheres assuming uniform lung distribution.

Objective:To assess the incidence of clinical and imaging radiation pneumonitis (RP) in a cohort of patients treated with >30 Gy cumulative lung dose (CLD) using Y90 microspheres. Materials and Methods:Four hundred three patients were treated with Y90 microspheres during a 4-year period. Of these, 58 patients received >30 Gy CLD. Patients were followed for toxicities suggestive of imaging or clinical RP. Toxicities were graded using the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. Patients were also followed for survival from time of first treatment. Results:There were 44 men and 14 women. Forty-three patients had hepatocellular carcinoma (HCC), whereas 15 had liver metastases. Mean and median follow-up were 7.3 and 6.0 months, respectively. Mean lung shunt fraction was slightly greater in the patients with HCC versus metastases (20% vs. 16.7%, P = 0.2308). The lifetime CLD for metastases and HCC groups were not statistically different (54.04 Gy vs. 48.44 Gy, P = 0.4303). Forty-three of 53 patients demonstrated no lung imaging findings suggestive of pneumonitis. Imaging findings in 10 patients included pleural effusions, atelectasis, and ground glass attenuation. There were no cases of clinical or imaging RP. Survival varied depending on stage as well as single and CLD. None of the patient deaths were attributed to respiratory compromise. Conclusion:RP was not predicted using the currently used Y90 dosimetry models that assume uniform distribution in the lungs. Further investigation and dose escalation studies are required to more precisely define the radiation tolerance of lung parenchyma using this mode of therapy.

The role of esophageal stents in the management of esophageal anastomotic leaks and benign esophageal perforations.

Objective:The aim of this review was to assess the safety and effectiveness of esophageal stents in the management of benign esophageal perforation and in the management of esophageal anastomotic leaks. Background:Benign esophageal perforation and postoperative esophageal anastomotic leak are often encountered. Endoscopic placement of esophageal stent across the site of leakage might help control the sepsis and reduce the mortality and morbidity. Methods:All the published case series reporting the use of metallic and plastic stents in the management of postoperative anastomotic leaks, spontaneous esophageal perforations, and iatrogenic esophageal perforations were identified from MEDLINE, EMBASE, and PubMed (1990-2012). Primary outcomes assessed were technical success rates and complete healing rates. Secondary outcomes assessed were stent migration rates, stent perforation rates, duration of hospital stay, time to stent removal, and mortality rates. A pooled analysis was performed and subgroup analysis was performed for plastic versus metallic stents and anastomotic leaks versus perforations separately. Results:A total of 27 case series with 340 patients were included. Technical and clinical success rates of stenting were 91% and 81%, respectively. Stent migration rates were significantly higher with plastic stents than with metallic stents (40/148 vs 13/117 patients, respectively; P = 0.001). Patients with metallic stents had significantly higher incidence of postprocedure strictures (P = 0.006). However, patients with plastic stents needed significantly higher number of reinterventions (P = 0.005). Mean postprocedure hospital stay varied from 8 days to 51 days. There was no significant difference in the primary or secondary outcomes when stenting was performed for anastomotic leaks or perforations. Conclusions:Endoscopic management of esophageal anastomotic leaks and perforations with the use of esophageal stents is technically feasible. It seems to be safe and effective when performed along with mediastinal or pleural drainage. Esophageal stent can, therefore, be considered as a treatment option in the management of patients who present early after esophageal perforation or anastomotic leak with limited mediastinal or pleural contamination.